Our aim is to gain a better understanding of the structural features necessary for agonist and antagonist activity at alpha-adrenoceptros. The proposed work is centered around the use of imidazoline derivatives as molecules to probe the stereochemical requirement for alpha-adrenoceptors. Recently, alpha-adrenoceptors have been subclassified alpha 1 and alpha 2, and little data is available which attempts to characterize and to optimize the interaction of imidazoline drugs with the different alpha-adrenoceptors. Our specific aims are (1) to design, synthesize, isolate and characterize a series of imidazoline analogs, (2) in those instances where appropriate, to separate geometrical isomers and resolve optical isomers for their respective biological studies, (3) to carry out pharmacological studies on the imidazoline derivatives on selected tissues in vitro, and in vivo to quantitative significant activity on the alpha-adrenoceptor subtypes, (4) to examine the imidazoline optical isomer analogs on alpha-adrenoceptors to see what the relationship is to the classical Easson-Stedman Hypothesis for phenethanolamines, (5) to examine the effects of cross desensitization and of selected group reagents in an attempt to differentiate between the action of imidazoline and phenethanolamine derivatives at alpha-adrenoceptors, (6) to initiate studies to evaluate the action of imidazoline analogs on thymidine incorporation into primary hepatocyte cultures that contain alpha 1-adrenoceptors which regulate cell growth, and (7) to determine for these molecules possessing significant alpha-adrenoceptor activities a profile of pharmacological activity including beta-adrenoceptor (beta 1 and beta 2) and histamine (H-1 and H-2) receptors. The studies should provide new insights into what effects substitutions have on known imidazoline agonist and antagonist and provide new findings as to the stereochemical requirements for alpha 1 and alpha 2-adrenoceptors. These drugs will enhance our understanding of the structural requirements for the subtypes of adrenoceptors and provide a more selective emans of treating nasal congestion, depresion, liver cell degeneration or proliferation, hypertension, hypotension and cardiovascular disorders.